Amyotrophic lateral sclerosis: Therapeutic potential of graphene quantum dots

Prevention of stress-mediated TDP-43 aggregation by GQDs. (A) Immunocytochemical analyses revealed that a 30 h treatment with 10 μM sodium arsenite (SA)-induced cytoplasmic aggregation of TDP-43 and coincubation of GQDs (1 μg/mL) prevented aggregation in HeLa cells. The endogenous TDP-43 (green) and G3BP1 (red) aggregates per cell (blue for DAPI) were analyzed from each image (n = 10) and compared with untreated control cells (Con). Scale bar: 10 μm. (B) Elimination of the aggregated TDP-43 by GQDs was analyzed. The cytosolic aggregation of TDP-43 was significantly reduced after 1 h of incubation of GQDs in the SA-pretreated HeLa cells. The endogenous TDP-43 (green) and G3BP1 (red) aggregates per cell were analyzed for each image (n = 10) and compared with untreated control cells (Con). Scale bar: 10 μm. The significance was assessed by a one-way ANOVA followed by Tukey’s posthoc test. (C) Aggregation of the C-terminal fragment (CTF) mutants of TDP-43 was prevented by treatment with GQDs. The HeLa cells transfected with EGFP-tagged full-length (WT) or each CTF for 48 h exhibited cytosolic aggregation without any stress, while the incubation of GQDs (1 μg/mL) significantly reduced the aggregations. The EGFP-tagged TDP-43 (green) and G3BP1 (red) aggregates per cell (blue for DAPI) were analyzed from each image (n = 10) and compared with control (transfected with a vehicle vector, Con). Scale bar: 10 μm. The significance was assessed by a two-way ANOVA followed by Šídák’s posthoc test. **P < 0.01 and ***P < 0.001. @ ACS Nano 2025, https://pubs.acs.org/doi/10.1021/acsnano.4c15283

A joint group of researchers from the Seoul National University, the Korea Brain Research Institute, and the Dong-A University has developed a major development for Lou Gehrig's disease. Graphene quantum dots (GQDs) have been shown by researchers to be effective against Lou Gehrig's disease (also known as amyotrophic lateral sclerosis, or ALS) in animal models in which proteinopathy is involved in the pathology. GQDs, therefore, represent a novel potential therapeutic strategy for ALS, noted the study published in ACS Nano.

GQDs and TDP-43 proteinopathy

In the context of ALS, TDP-43 proteinopathy is defined by the aberrant phase separation and stress granule-mediated cytosolic aggregation of TDP-43 in motor neurons. These results show how GQDs can modulate TDP-43 aggregation from both the stress granules dynamics and phase separation perspectives. The researchers demonstrated that GQDs directly bind to TDP-43 inhibiting amyloid fibril formation while reducing cytosolic TDP-43 aggregation in motor neurons.

In vivo studies and clinical feasibility

The therapeutic effects of GQDs were additionally confirmed in vivo in TDP-43 transgenic mice. Treatment with GQDs significantly postponed the symptoms of ALS, greatly extending the mice's lifespan. They also saw an increase in motor neuron survival, less glial activation and a reduced cytosolic aggregation of TDP-43 in treated mice. In addition, the team showed GQDs' clinical feasibility for other types of ALS caused by FUS and C9orf72, indicating the potential widespread application of this therapeutic approach.

Decoding the mechanism of action

To characterize the mechanism by which GQDs exert therapeutic effect, the researchers carried out in vitro studies using recombinant TDP-43 protein and its C-terminal fragments. They demonstrated that GQDs bind specifically to the intrinsically disordered region (IDR) of TDP-43, which elicits its aggregation. This binding interaction prevents the formation of amyloid fibrils further diminishing TDP-43 aggregation. To gain further insights into the mechanism of action, the team also characterized the thermodynamic parameters of the interaction between GQDs and TDP-43 peptides using isothermal titration calorimetry (ITC).

Drug development and future research implications

The researchers hope that the findings described in their study, combined with further investigation of the therapeutic potential of GQDs in clinical trials, will eventually lead to the development of effective therapies for patients with ALS. Thus, future investigations will aim to optimize the delivery of GQDs to the central nervous system and the potential to target additional proteinopathies involved in neurodegeneration. Reference Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis

Na Young Park, Yunseok Heo, Ji Won Yang, Je Min Yoo, Hye Ji Jang, Ju Hee Jo, Su Jeong Park, Yuxi Lin, Joonhyeok Choi, Hyeonjin Jeon, Sun Joo Cha, Gaeun Bae, Donghoon Kim, Juhee Kim, Wade Zeno, Jong Bo Park, Noriyoshi Isozumi, Tomohide Saio, Seung Hyun Kim, Hojae Lee, Byung Hee Hong, Minyeop Nahm, Young-Ho Lee, Young Bin Hong https://pubs.acs.org/doi/10.1021/acsnano.4c15283 Nanotechnology World (NW)